Physiological consequences of over- or under-expression of fibrinolytic system components in transgenic mice.

Studies with transgenic mice over- or under-expressing components of the fibrinolytic system, have revealed a significant role of this system in fibrin clot surveillance, reproduction, (vascular) wound healing, brain function, health and survival. The distinct phenotypes associated with single loss and the more severe phenotype associated with combined loss of plasminogen activator gene function suggest that through evolution, both plasminogen activators have evolved with specific but overlapping biological properties. Interestingly, the role of the fibrinolytic system in thrombosis and vascular wound healing became more apparent after challenging mice single deficiencies of plasminogen activators with an inflammatory, or traumatic challenge, respectively. It therefore seems warranted to examine possible consequences of loss of plasminogen activator gene function in other processes including atherosclerosis, neoangiogenesis, inflammatory lung and kidney disease and malignancy. The plasminogen activator knock-out mice with their thrombotic phenotypes are also valuable models to evaluate whether adenoviral mediated gene-transfer of wild-type or mutant plasminogen activator genes is able to restore normal thrombolytic function and to prevent thrombosis. Preliminary evidence suggests that impaired thrombolysis of t-PA deficient mice can be completely restored using adenoviral-mediated gene transfer of rt-PA (Carmeliet et al, 1994c). In addition, analysis of neointima formation in plasminogen activator deficient mice suggests that controlled reduction of fibrinolytic activity in the vessel wall might be beneficial for the prevention or reduction of restenosis. Whether this can be achieved with gene transfer methodologies remains to be defined.